Compositions and methods for the treatment or prevention of inflammation

ABSTRACT

The present invention relates to compounds containing as active ingredients hyaluronic acid and polyvinylpyrrolidone, for the treatment of inflammatory, ulcerative and painful conditions of moist epithelial surfaces such as mucositis, stomatitis, vestibulitis, aphthous ulcerations, and Behcet&#39;s syndrome.

[0001] The present application is a continuation-in-part of Pennie &Edmonds LLP Docket No.10142-007, filed on Feb. 21, 2002, which claimspriority benefits of International Patent Application No. PCT/EP01/08303filed Jul. 18, 2001, (published as WO 02/09637 in English on Feb. 7,2002), which in turn claims priority benefits of Italian PatentApplication No. MI 2000 A 001732, filed Jul. 28, 2000, the disclosuresof each of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to certain compositions useful for themanagement of painful ulcerative and inflammatory conditions of moistsurfaces including the mouth, oropharynx, oesophagus, vagina and rectum(including, but not limited to, mucositis, stomatitis, aphthousulcerations, and Behcet's syndrome).

BACKGROUND OF THE INVENTION

[0003] Aggressive cancer treatment may have toxic effects on normalcells as well as cancer cells. The gastrointestinal tract, including themouth, is especially affected because these cells are replaced by thebody continuously.

[0004] Mucositis, an inflammation of the mucous membranes in the mouth,is one of the most common oral problems occurring after chemotherapy andradiation therapy. Mucositis can contribute to oral infections,inability to taste normally and pain arising from the resulting opensores that can develop. Mucositis can become so painful that the patientwill not eat or drink, contributing to dehydration and malnutrition.

[0005] Radiation therapy to the head and neck for cancers in those areascommonly injure saliva glands and the inside of the mouth which cancause dry mouth, leading to dental disease.

[0006] The mucositis problem is not restricted to cancer patients, asmucositis frequently also occurs in HIV patients, particularly whenassociated with Kaposi's sarcoma, in patients affected withnon-Hodgkin's lymphoma, in debilitated elderly patients and in patientsreceiving BRM treatments like interleukin-2, TNF, interferons,lymphokine-activated lymphocytes and the like.

[0007] Such oral problems may make it difficult for the cancer or AIDSpatient to receive a complete dose of chemotherapy or radiation therapy.Sometimes treatment must be stopped completely. Such problems are notinfrequent: about half of the patients have severe oral lesions thatrequire medical intervention, mostly involving the changes in cancermedication or treatment mentioned above.

[0008] Current therapies for mucositis are limited. Cleaning the mouthis recommended to retard the progression of the condition.

[0009] Oral cleaning care includes gently cleaning the mouth,moisturizing the lips and mouth, and relieving pain and swelling. A softtoothbrush or toothette cleans teeth well and gently. Cleansing agentscan include “salt and soda” (½ tsp. salt and 2 Tbs. of sodiumbicarbonate in 32 oz. of warm water), normal saline, sterile water, orsodium bicarbonate (1 tsp. in 8 oz of water). Hydrogen peroxide dilutedin equal amounts of water or weak salt water can be used when crustingis present. (This should be used for 1 or 2 days only because it willkeep mucositis from healing.) Gentle wiping with a wet gauze dipped insalt water helps remove particles. Toothettes may be too rough for someareas. Particles should be removed before ointments or other medicationsare put onto the gums or tissues. Rinsing often cleans and moistens thetissues, prevents crusting, and soothes sore gums and tissues.

[0010] Frequent rinsing prevents particles and bacteria from collectingin the mouth. A salt and baking soda solution neutralizes acids anddissolves thick saliva.

[0011] Capsaicin, the active ingredient in hot peppers, reportedly hasused to increase a person's ability to tolerate pain. When capsaicin isput on inflamed tissues in the mouth, mucositis pain may decrease as theburning feeling from the capsaicin decreases. Capsaicin is only beingused experimentally; however, all side effects are not known.

[0012] Mostly, physicians have resorted ice chips or to rather makeshiftmixtures of benzocaine with kaopectate and the like. These approachesprovide rather limited, temporary relief.

[0013] Carrington Laboratories of Irving, Tex. has sold a mucositisproduct called “Radiacare” for a number of years. However, this producthas made limited inroads into the marketplace, and thus has provided fewpatients relief from the symptoms of mucositis.

[0014] Many women get oral aphthous ulceration at specific times of themenstrual cycle and simultaneously get the same kind of ulcers in thegenital tract, in particular the vulva and vagina. This is sometimesvery severe and can cause retention of urine and require strongpainkillers and sedatives. The most severe form is called Behcet'ssyndrome.

[0015] The terms mucositis and stomatitis are often used interchangeablybut may include some general distinctions. Mucositis describes a toxicinflammatory reaction affecting the gastrointestinal tract, which mayresult from exposure to chemotherapeutic agents or ionising radiation.Mucositis typically manifests as an erythematous, burn-like lesion or asrandom, focal-to-diffuse, ulcerative lesions. Stomatitis refers to aninflammatory reaction affecting the oral mucosa, with or withoutulceration, that may be caused or intensified by pharmacological,particularly chemotherapeutic treatments, or by radiotherapy. Stomatitiscan range from mild to severe; the patient with severe stomatitis isunable to take anything by mouth.

[0016] Thus, there is a clear need for compositions and methods usefulfor treating or preventing inflammation, including but not limited to,mucositis, stomatitis, aphthous ulcerations, Behcet's syndrome, etc.

[0017] Citation of a reference in this or any section of thespecification shall not be construed as an admission that such referenceis prior art to the present invention.

SUMMARY OF THE INVENTION

[0018] The present invention is directed to a composition comprisingfrom about 0.01 to about 5 percent by weight of hyaluronic acid, or apharmaceutically acceptable salt thereof, having a molecular weight fromabout 1.6 and 2.2 million daltons; from about 0.04 to about 15% byweight of a K60 to K100 polyvinylpyrrolidone; and from about 86 to about98% water. In one embodiment, the viscosity of the composition is fromabout 50 to about 500 centipoise. In an embodiment thepolyvinylpyrrolidone is from about K85 to about K95 and is from about 3to about 10% by weight of the composition. In another embodiment, thepolyvinylpyrrolidone is from about 7 to about 10% by weight of thecomposition. In yet another embodiment, the hyaluronic acid, or thepharmaceutically acceptable salt thereof, is from about 1.8 to about 2.0million daltons, and from about 0.01 to about 2% by weight of thecomposition, and wherein the viscosity of the composition is from about90 to about 1000 centipoise. In yet another embodiment, the hyaluronicacid, or the pharmaceutically acceptable salt thereof, is from about 1.8to about 2.0 million daltons and from about 0.01% to about 2% by weightof the composition. In an embodiment, the viscosity of the compositionis from about 90 to about 1000 centipoise. In a preferred embodiment,the composition is in the form of a gel.

[0019] The present invention is also directed to a compositioncomprising from about 0.04 to about 5 percent by weight of hyaluronicacid, or a pharmaceutically acceptable salt thereof, with a molecularweight from about 1.6 to about 2.2 million daltons; from about 0.08 toabout 15% by weight of a K60 to K100 polyvinylpyrrolidone; and fromabout 86 to about 98% water. In one embodiment, the viscosity of thecomposition is from about 50 to about 500 centipoise. In an embodiment,the polyvinylpyrrolidone, is from about K85 to about K95, and is fromabout 6 to about 12% by weight of the composition. In anotherembodiment, the polyvinylpyrrolidone is from about 8 to about 10% byweight of the composition. In yet another embodiment, the hyaluronicacid, or the pharmaceutically acceptable salt thereof, is from about 1.8to about 2.0 million daltons and from about 0.04 to about 2% by weightof the composition. In yet another embodiment, the hyaluronic acid, orthe pharmaceutically acceptable salt thereof, is from about 1.8 to about2.0 million daltons and from about 0.04 to about 2% by weight of thecomposition. In a preferred embodiment, the composition is in the formof a gel.

[0020] The present invention is also directed to a flexible packetcomprising a composition comprising from about 0.04 to about 5 percentby weight of hyaluronic acid, or a pharmaceutically acceptable saltthereof, with a molecular weight from about 1.6 to about 2.2 milliondaltons; from about 0.08 to about 15% by weight of a K60 to K100polyvinylpyrrolidone; and from about 86 to about 98% water. In oneembodiment, the viscosity of the composition is from about 50 to about500 centipoise. In a preferred embodiment, the packet is a sealed pouchcomprising from about 10 to about 30 milliliters of the composition. Thepresent invention is also directed to a flexible packet comprising acomposition comprising hyaluronic acid, or a pharmaceutically acceptablesalt thereof, glycyrrhetinic acid, or a pharmaceutically acceptable saltthereof, and polyvinylpyrrolidone.

[0021] The present invention is also directed to a compositioncomprising hyaluronic acid, or a pharmaceutically acceptable saltthereof, glycyrrhetinic acid, or a pharmaceutically acceptable saltthereof, and polyvinylpyrrolidone. In an embodiment, the compositionfurther comprises a viscosity-increasing agent, surfactant, stabilizingagent/preservative, flavor, fragrance, sweetening agent, bioadhesiveagent, or a co-solubilizer. The composition may also further comprise acellulose derivative, acrylic or methacrylic acid polymer or copolymer,ethylene or propylene glycol, polyethoxylated hydrogenated castor oil,EDTA, sodium benzoate, sodium or potassium sorbate, dextrin, sodiumsaccharin, or aspartame. In yet another embodiment, the compositionfurther comprises an antibacterial agent, disinfectant agent, antifungalagent, analgesic, anti-inflammatory, emollient, or a local anesthetic.

[0022] The present invention is also directed to a method for treatingor preventing inflammation in a patient comprising administering to apatient in need thereof an effective amount of a composition comprisingfrom about 0.01 to about 5 percent by weight of hyaluronic acid, or apharmaceutically acceptable salt thereof, having a molecular weight fromabout 1.6 to about 2.2 million daltons; from about 0.04 to about 15% byweight of a K60 to K100 polyvinylpyrrolidone; and from about 86 to about98% water. In one embodiment, the viscosity of the composition is fromabout 50 to about 500 centipoise. In an embodiment, the composition isadministered at least twice daily for at least two consecutive days. Inyet another embodiment, the composition is administered at least threetimes daily for at least four consecutive days. In yet anotherembodiment, the composition is administered at least three times dailyfor at least seven consecutive days. The present invention is alsodirected to a method for treating or preventing inflammation in apatient, comprising administering to a patient in need thereof aneffective amount of a composition comprising hyaluronic acid, or apharmaceutically acceptable salt thereof, glycyrrhetinic acid, or apharmaceutically acceptable salt thereof, and polyvinylpyrrolidone. Inan embodiment, the composition is administered at least twice daily forat least two consecutive days. In yet another embodiment, thecomposition is administered at least three times daily for at least fourconsecutive days. In yet another embodiment, the composition isadministered at least three times daily for at least seven consecutivedays. In addition to its ordinary meaning, the term treatmentencompasses inhibition of progression of symptoms or amelioration ofsymptoms of inflammation and mucositis.

[0023] The present invention is also directed to a method for treatingor preventing inflammation in the oral cavity of a patient comprisinghaving a patient in need thereof gargle an effective amount of acomposition comprising from about 0.01 to about 5 percent by weight ofhyaluronic acid, or a pharmaceutically acceptable salt thereof, having amolecular weight from about 1.6 to about 2.2 million daltons; from about0.04 to about 15% by weight of a K60 to K100 polyvinylpyrrolidone; andfrom about 86 to about 98% water.

[0024] In one embodiment, the viscosity of the composition is from about50 to about 500 centipoise. The present invention is also directed to amethod for treating or preventing inflammation in the oral cavity of apatient comprising having a patient in need thereof gargle an effectiveamount of a composition comprising hyaluronic acid or a pharmaceuticallyacceptable salt thereof; glycyrrhetinic acid or a pharmaceuticallyacceptable salt thereof; and polyvinylpyrrolidone.

[0025] The present invention is directed to a method for treating orpreventing mucositis in a patient comprising administering to a patientin need thereof an effective amount of a composition comprising fromabout 0.01 to about 5 percent by weight of hyaluronic acid, or apharmaceutically acceptable salt thereof, having a molecular weight fromabout 1.6 to about 2.2 million daltons; from about 0.04 to about 15% byweight of a K60 to K100 polyvinylpyrrolidone; and from about 86 to about98% water. In one embodiment, the viscosity of the composition is fromabout 50 to about 500 centipoise. The present invention is also directedto a method for treating or preventing mucositis in a patient comprisingadministering to a patient in need thereof an effective amount of acomposition comprising hyaluronic acid or a pharmaceutically acceptablesalt thereof; glycyrrhetinic acid or a pharmaceutically acceptable saltthereof; and polyvinylpyrrolidone.

[0026] The present invention is directed to a method for treating painresulting from oral surgery in a patient in need thereof comprisinghaving a patient in need thereof gargle an effective amount of acomposition comprising from about 0.01 to about 5 percent by weight ofhyaluronic acid, or a pharmaceutically acceptable salt thereof, having amolecular weight from about 1.6 to about 2.2 million daltons; from about0.04 to about 15% by weight of a K60 to K100 polyvinylpyrrolidone; andfrom about 86 to about 98% water. In one embodiment, the viscosity ofthe composition is from about 50 to about 500 centipoise. The presentinvention is also directed to a method for treating pain resulting fromoral surgery in a patient in need thereof comprising having a patient inneed thereof gargle an effective amount of a composition comprisinghyaluronic acid or a pharmaceutically acceptable salt thereof;glycyrrhetinic acid or a pharmaceutically acceptable salt thereof; andpolyvinylpyrrolidone.

[0027] The present invention can be more fully explained by reference tothe following detailed description and illustrative examples.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Surprisingly, the topical administration of a formulationcomprising an effective amount of hyaluronic acid, or a pharmaceuticallyacceptable salt thereof, and polyvinylpyrrolidone provides an effectivetherapeutical or preventive treatment for mucositis and stomatitis ofvarious origin and severity and, more generally, of the lesions of theoro-pharynx cavity and oesophagus, particularly those caused by dentaldevices and by radio- or chemotherapy and by surgery.

[0029] Without being bound by a particular mode of action, the favorabletherapeutic results obtained by the use of the compositions of thepresent invention are believed to be due to both the interactionsbetween hyaluronic acid, or a pharmaceutically acceptable salt thereof,and polyvinylpyrrolidone, and the capability of the formulation ofadhering to the oral mucosa providing a protective coating for theexposed nerve endings, and thus, reduction of pain and promotingcicatrisation and healing of the lesions. Furthermore, it is believedthat the moisturizing effect of the compositions has beneficial effectas it protects mucous membranes from further irritating lesions.

[0030] In one embodiment, the present invention involves a compositioncomprising from about 0.01 to about 5 percent by weight of hyaluronicacid, or a pharmaceutically acceptable salt thereof, having a molecularweight from about 1.6 to about 2.2 million daltons; from about 0.04 toabout 15% by weight of a K60 to K100 polyvinylpyrrolidone; and fromabout 86 to about 98% water. In one embodiment, the viscosity of thecomposition is from about 50 to about 500 centipoise.

[0031] In an alternative embodiment, the present invention involves acomposition comprising from about 0.04 to about 5 percent by weight ofhyaluronic acid, or a pharmaceutically acceptable salt thereof, having amolecular weight from about 1.6 to about 2.2 million daltons; from about0.08 to about 15% by weight of a K60 to K100 polyvinylpyrrolidone; andfrom about 86 to about 98% water. In one embodiment, the viscosity ofthe composition is from about 50 to about 500 centipoise. Thecompositions of the present invention can be diluted with water, andaccordingly, is useful for obtaining the above compositions. In analternative embodiment, the composition can be diluted withphysiological saline.

[0032] These compositions can be used by themselves or in admixture withone or more medicaments, excipients and/or adjuvants, preferably forminga viscous and lubricating substance that remains adherent to the surfaceepithelium. These compositions are suitable for topical administrationto epithelial surfaces such as, but not limited to, the oropharynx andoesophagus.

[0033] A further aspect of the invention concerns the use of hyaluronicacid, or a pharmaceutically acceptable salt thereof, glycyrrhetinicacid, or a pharmaceutically acceptable salt thereof, andpolyvinylpyrrolidone for treating or preventing inflammation in apatient. In one embodiment, the inflammation is of epithelial surfacessuch as, but not limited to, the oral mucosa, particularly mucositis andstomatitis.

[0034] Preferably, the compositions of the present invention areadministered by topical application. In a particular embodiment in whichthe composition is administered to the oral cavity, the patient, aftergargling with the composition, and if desired, may refrain from eatingor drinking for a certain time, ranging from minutes up to hours aftergargling. Alternatively, the patient, if desired, may eat or drinkimmediately after gargling.

[0035] The compositions of the invention are preferably in the form of aslightly viscous aqueous liquid (gel) which provides a film-forming andcoating effect on the epithelial surfaces such as, but not limited tothe oral mucosa.

[0036] As explained above, the present invention relates to acomposition comprising from about 0.01 to about 5 percent by weight ofhyaluronic acid, or a pharmaceutically acceptable salt thereof, having amolecular weight from about 1.6 and 2.2 million daltons; from about 0.04to about 15% by weight of a K60 to K100 polyvinylpyrrolidone; and fromabout 86 to about 98% water. In one embodiment, the viscosity of thecomposition is from about 50 to about 500 centipoise. In an embodiment,the polyvinylpyrrolidone is from about K85 and K95 and is from about 3and 10% by weight of the composition. Most preferably, thepolyvinylpyrrolidone is from about 7 to about 10% by weight of thecomposition. Preferably, the hyaluronic acid, or the pharmaceuticallyacceptable salt thereof, is from about 1.8 to about 2.0 million daltonsand from about 0.01 to about 2% by weight. In one embodiment, theviscosity of the composition is from about 90 to about 1000 centipoise.Preferably, the composition is in the form of a gel. Most preferably,the hyaluronic acid, or the pharmaceutically acceptable salt thereof, isfrom about 1.8 to about 2.0 million daltons and from about 0.01 to about2% by weight of the composition, the viscosity of the composition isfrom about 90 to about 1000 centipoise and the composition is in theform of a gel. Further, glycyrrhetinic acid, or a pharmaceuticallyacceptable salt thereof, can be present in weight percentages rangingfrom about 0.01 to about 3% by weight of the composition.

[0037] The viscosity of the compositions can be measured using routinemethods. In particular, viscosity can be measured using a BrookfieldModel DV1+ viscometer (Middleboro, Mass.) at room temperature,preferably at about 22°-25° C., or using a Haake Model VT02 viscometer(Karlsruhe, Germany) at room temperature, preferably at about 22°-25° C.

[0038] In a particular embodiment of the present invention, thecompositions are provided in a concentrated form for later dilution withwater. The compositions comprise from about 0.04 to about 5 percent byweight of hyaluronic acid, or a pharmaceutically acceptable saltthereof, having a molecular weight from about 1.6 to about 2.2 milliondaltons; from about 0.08 to about 15% by weight of a K60 to K100polyvinylpyrrolidone; and from about 86 to about 98% water. In oneembodiment, the viscosity of the composition is from about 50 to about500 centipoise. These compositions preferably comprisepolyvinylpyrrolidone from about K85 to about K95 and from about 6 toabout 12% by weight of the composition, most preferably from about 8 toabout 10% by weight of the composition; and comprise hyaluronic acid, ora pharmaceutically acceptable salt thereof, having a molecular weightfrom about 1.8 to about 2.0 million daltons and from about 0.04 to about2% by weight of the composition. Preferably, hyaluronic acid, or thepharmaceutically acceptable salt thereof, is from about 1.8 to about 2.0million daltons in molecular weight and from about 0.04 to about 2% byweight of the composition.

[0039] Examples of pharmaceutically acceptable salts include, but arenot limited to, sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound having an acidic functional group, such as a carboxylic acid orsulfonic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N, N,-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

[0040] The compositions of the present inventions can comprise apharmaceutically acceptable excipient, preferably for topicaladministration, such as one or more of the following:

[0041] viscosity-increasing agent;

[0042] surfactant;

[0043] stabilizing agent/preservative;

[0044] flavor, fragrance, sweetening agent;

[0045] bioadhesive;

[0046] co-solubilizer.

[0047] Examples of said excipients comprise cellulose derivatives,acrylic or methacrylic acids polymers or copolymers, ethylene orpropylene glycols, polyethoxylated hydrogenated castor oil, EDTA, sodiumbenzoate, sodium or potassium sorbate, dextrins, sodium saccharin,aspartame and other excipients conventionally used in the formulation ofcollutories or liquid oral forms. Oral formulation can include standardcarriers such as pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,etc. Additional examples of suitable excipients are described in“Remington's Pharmaceutical Sciences” by E. W. Martin.

[0048] The compositions of the present invention may further compriseone or more other active ingredients, such as an antibacterial,disinfectant, antifungal, analgesic, other anti-inflammatory,emollients, local anaesthetics and the like. Suitable antimicrobialsinclude, but are not limited to, quaternary ammonium salts such asbenzalkonium chloride.

[0049] The precise dose to be employed in the composition will depend onthe route of administration, and the seriousness of the disease ordisorder, and should be decided according to the judgment of thepractitioner and each patient's circumstances. In principle, however,for oral applications, a wash or gargle with 10-50 ml of solution,optionally diluted in water, for a time of about up to two or threeminutes at least two but preferably three times or more daily, mostpreferably before meals, will be sufficient to provide an optimaltherapeutic or preventive response. The treatment can be protracteduntil remission of symptoms, usually for at least 2 days, but preferably5-10 days. More prolonged treatments are not contraindicated,considering the low, if any, toxicity of the components of theformulations of the invention.

[0050] The present invention also provides a pharmaceutical pack or kitcomprising one or more containers, e.g., a flexible packet, vial,ampoule, bottle and the like, filled with one or more of the ingredientsof the compositions of the invention. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

[0051] In a preferred embodiment, the compositions of the presentinvention can be presented as single- or multi-dose forms in a flexiblepacket. Preferably, the compositions of the present invention arepackaged in the concentrated form in flexible packets with a dose offrom about 10 to about 30 ml per packet that can be diluted with waterto create about 40-60 ml of product for use by the patient.

[0052] The following series of examples are presented by way ofillustration and not by way of limitation on the scope of the invention.

EXAMPLE 1

[0053] Qualitative-quantitative composition percent composition:Ingredient % By Weight Sodium hyaluronate 0.1 Glycyrrhetinic acid 0.06PYP (K60 to K100) 9.0 Maltodextrin 6.00 Propylene glycol 2.94 Potassiumsorbate 0.3 Sodium benzoate 0.3 Hydroxyethyl cellulose 1.5 Hydrogenatedcastor oil PEG-40 0.27 Disodium EDTA 0.1 Benzalkonium chloride 0.5Perfume (Glycyrrhiza Comp. 2717) 0.16 Sodium saccharin 0.1 Depuratedwater 78.44

[0054] To prepare this composition, water was placed in aturboemulsifier, then a mixture of potassium sorbate, sodium benzoateand disodium EDTA was added, followed by hyaluronic acid andmaltodextrin. The mixture was stirred after each addition until completedissolution of the components. After that, PVP was slowly added understirring and vacuum (30 mm Hg) until complete salvation. Then sodiumsaccharin and hydroxyethylcellulose were subsequently added, the wholewas subjected to vacuum and left under stirring until completesolvation. Afterwards, hydrogenated castor oil 40/OE and perfume,benzalkonium chloride, and a mixture of propylene glycol andglycyrrhetinic acid were added in that order, stirring after eachaddition until complete dissolution of the components. When theadditions were completed, the mixture was stirred under vacuum for 30minutes.

[0055] For a concentrated version of the invention, 10 ml or 15 ml ofthe above composition were distributed in a packet or mono-dose vial,which can be diluted with 30-50 ml of water before use; for theready-to-use version, the composition disclosed above was diluted withdepurated water to a concentration of 50%, and 200 ml or 300 ml of theresulting composition were distributed in bottles.

EXAMPLE 2

[0056] In Vivo Data

[0057] Thirty patients, of age range from 30 to 60 years, wereevaluated, 10 of them were AIDS patients 30 to 40 years of age who werealso receiving anti-retroviral therapy. All patients in the study wereaffected with inflammatory pathologies of the oral cavity of variousaetiology:

[0058] 12 cases of oro-pharyngeal mucositis;

[0059] 4 cases of aphthous lesions of the oral cavity;

[0060] 4 cases of post-traumatic lesions;

[0061] 3 cases of Lichen Planus of the oral cavity;

[0062] 3 cases of radiotherapy-induced stomatitis;

[0063] 3 cases of oral cavity surgery side effects; and

[0064] 1 case of leukoplakia.

[0065] Patients were treated with the composition described in Example 1in 15 ml sachets (packets) diluted in water in a 1:4 ratio. The slightlyviscous solution was retained in the mouth for 2-3 minutes during whichit was gargled and swirled about to obtain homogeneous distribution onthe whole surface of the oral mucosa. The solution was then discharged.The patients refrained from eating or drinking for various times aftergargling ranging from immediately after gargling to more than 1 hourafter gargling.

[0066] The formulation was used three times a day 60 minutes before mealtimes for seven consecutive days.

[0067] At the end of the treatment, the extent of inflammation andlesions, the decrease or disappearance of dysphagia for solid andsemi-solid foods, and liquids, and the duration of the activity of theproduct were evaluated.

[0068] After the first administration, more than 80% of patientsperceived within a few hours reduction of pain so as to permit foodintake. The effect lasted three or four hours.

[0069] Healing of the lesions of the oral mucosa occurred after 34 daysof treatment in about 60% of treated cases. The percentage reached 90%at the end of one week of treatment. In the remaining three cases only apathological condition persisted, but with improved symptoms comparedwith the beginning of the treatment, providing a remarkable improvementof life quality and restoring a normal, differentiated diet.

EXAMPLE 3

[0070] Two patients with throat pain (sore throat) were unable to obtainrelief with analgesics or other topical agents. Patients were treatedwith the composition described in Example 1 in 15 ml packets, thecontents of which were diluted in water in a 1:4 ratio. The solution wasretained in the mouth for about one minute during which time it wasgargled to obtain good contact with the tissues of the throat. Thesolution was then discharged. Within ten minutes, the patientsexperienced dramatic relief of their sore throat symptoms, which reliefpersisted for several hours.

[0071] The present invention is not to be limited in scope by thespecific embodiments described herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description andaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0072] Various publications are cited herein, the disclosures of whichare incorporated by reference in their entireties.

What is claimed is:
 1. A composition, comprising: from about 0.01 toabout 5 percent by weight of hyaluronic acid, or a pharmaceuticallyacceptable salt thereof, having a molecular weight from about 1.6 and2.2 million daltons; from about 0.04 to about 15% by weight of a K60 toK100 polyvinylpyrrolidone; and from about 86 to about 98% water, whereinthe viscosity of the composition is from about 50 to about 500centipoise.
 2. The composition of claim 1, wherein thepolyvinylpyrrolidone is from about K85 to about K95 and is from about 3to about 10% by weight of the composition.
 3. The composition of claim2, wherein the polyvinylpyrrolidone is from about 7 to about 10% byweight of the composition.
 4. The composition of claim 1, wherein thehyaluronic acid, or the pharmaceutically acceptable salt thereof, isfrom about 1.8 to about 2.0 million daltons, and from about 0.01 toabout 2% by weight of the composition, and wherein the viscosity of thecomposition is from about 90 to about 1000 centipoise.
 5. Thecomposition of claim 4, in the form of a gel.
 6. The composition ofclaim 3, wherein the hyaluronic acid, or the pharmaceutically acceptablesalt thereof, is from about 1.8 to about 2.0 million daltons and fromabout 0.01% to about 2% by weight of the composition, and wherein theviscosity of the composition is from about 90 to about 1000 centipoise.7. The composition of claim 6, in the form of a gel.
 8. The compositionof claim 1, further comprising a viscosity-increasing agent, surfactant,stabilizing agent/preservative, flavour, fragrance, sweetening agent,bioadhesive agent, or a co-solubilizer.
 9. The composition of claim 8,further comprising a cellulose derivative, acrylic or methacrylic acidpolymer or copolymer, ethylene or propylene glycol, polyethoxylatedhydrogenated castor oil, EDTA, sodium benzoate, sodium or potassiumsorbate, dextrin, sodium saccharin, or aspartame.
 10. The composition ofclaim 1, further comprising an antibacterial agent, disinfectant agent,antifungal agent, analgesic, anti-inflammatory, emollient, or a localanesthetic.
 11. The composition of claim 1, further comprisingglycyrrhetinic acid or a pharmaceutically acceptable salt thereof.
 12. Acomposition comprising: from about 0.04 to about 5 percent by weight ofhyaluronic acid, or a pharmaceutically acceptable salt thereof, with amolecular weight from about 1.6 to about 2.2 million daltons; from about0.08 to about 15% by weight of a K60 to K100 polyvinylpyrrolidone; andfrom about 86 to about 98% water, wherein the viscosity of thecomposition is from about 50 to about 500 centipoise.
 13. Thecomposition of claim 12, wherein the polyvinylpyrrolidone is from aboutK85 to about K95, and is from about 6 to about 12% by weight of thecomposition.
 14. The composition of claim 13, wherein thepolyvinylpyrrolidone is from about 8 to about 10% by weight of thecomposition.
 15. The composition of claim 12, wherein the hyaluronicacid, or the pharmaceutically acceptable salt thereof, is from about 1.8to about 2.0 million daltons and from about 0.04 to about 2% by weightof the composition.
 16. The composition of claim 15, in the form of agel.
 17. The composition of claim 14, wherein the hyaluronic acid, orthe pharmaceutically acceptable salt thereof, is from about 1.8 to about2.0 million daltons and from about 0.04 to about 2% by weight of thecomposition.
 18. The composition of claim 17, in the form of a gel. 19.The composition of claim 12, further comprising a viscosity-increasinggent, surfactant, stabilizing agent/preservative, flavour, fragrance,sweetening agent, bioadhesive agent, or a co-solubilizer.
 20. Thecomposition of claim 19, further comprising a cellulose derivative,acrylic or methacrylic acid polymer or copolymer, ethylene or propyleneglycol, polyethoxylated hydrogenated castor oil, EDTA,.sodium benzoate,sodium or potassium sorbate, dextrin, sodium saccharin, or aspartame.21. The composition of claim 12, further comprising an antibacterialagent, disinfectant agent, antifungal agent, analgesic,anti-inflammatory, emollient, or a local anesthetic.
 22. The compositionof claim 12, further comprising glycyrrhetinic acid or apharmaceutically acceptable salt thereof.
 23. A flexible packetcomprising the composition of claim
 12. 24. The packet of claim 23,being a sealed pouch comprising from about 10 to about 30 milliliters ofthe composition.
 25. A composition comprising hyaluronic acid or apharmaceutically acceptable salt thereof; glycyrrhetinic acid or apharmaceutically acceptable salt thereof; and polyvinylpyrrolidone. 26.A flexible packet comprising the composition of claim
 25. 27. Thecomposition of claim 25, further comprising a viscosity-increasing gent,surfactant, stabilizing agent/preservative, flavour, fragrance,sweetening agent, bioadhesive agent, or a co-solubilizer.
 28. Thecomposition of claim 27, further comprising a cellulose derivative,acrylic or methacrylic acid polymer or copolymer, ethylene or propyleneglycol, polyethoxylated hydrogenated castor oil, EDTA, sodium benzoate,sodium or potassium sorbate, dextrin, sodium saccharin, or aspartame.29. The composition of claim 25, further comprising an antibacterialagent, disinfectant agent, antifungal agent, analgesic,anti-inflammatory, emollient, or a local anesthetic.
 30. A method fortreating or preventing inflammation in a patient comprising:administering to a patient in need thereof an effective amount of acomposition comprising: (i) from about 0.01 to about 5 percent by weightof hyaluronic acid, or a pharmaceutically acceptable salt thereof,having a molecular weight from about 1.6 to about 2.2 million daltons;(ii) from about 0.04 to about 15% by weight of a K60 to K100polyvinylpyrrolidone; and (iii) from about 86 to about 98% water,wherein the viscosity of the composition is from about 50 to about 500centipoise.
 31. The method of claim 30, wherein the composition isadministered at least twice daily for at least two consecutive days. 32.The method of claim 30, wherein the composition is administered at leastthree times daily for at least four consecutive days.
 33. The method ofclaim 30, wherein the composition is administered at least three timesdaily for at least seven consecutive days.
 34. The method of claim 30,wherein the composition further comprises a viscosity-increasing agent,surfactant, stabilizing agent/preservative, flavour, fragrance,sweetening agent, bioadhesive agent, or a co-solubilizer.
 35. The methodof claim 34, wherein the composition further comprises a cellulosederivative, acrylic or methacrylic acid polymer or copolymer, ethyleneor propylene glycol, polyethoxylated hydrogenated castor oil, EDTA,sodium benzoate, sodium or potassium sorbate, dextrin, sodium saccharin,or aspartame.
 36. The method of claim 30, wherein the compositionfurther comprises an antibacterial agent, disinfectant agent, antifungalagent, analgesic, anti-inflammatory, emollient, or a local anesthetic.37. The method of claim 30, wherein the administration is by topicalapplication.
 38. The method of claim 30, wherein the composition furthercomprises glycyrrhetinic acid or a pharmaceutically acceptable saltthereof.
 39. A method for treating or preventing inflammation in apatient, comprising administering to a patient in need thereof aneffective amount of a composition comprising hyaluronic acid or apharmaceutically acceptable salt thereof; glycyrrhetinic acid or apharmaceutically acceptable salt thereof; and polyvinylpyrrolidone. 40.The method of claim 39, wherein the administration is by topicalapplication.
 41. The method of claim 39, wherein the composition isadministered at least twice daily for at least two consecutive days. 42.The method of claim 39, wherein the composition is administered at leastthree times daily for at least four consecutive days.
 43. The method ofclaim 39, wherein the composition is administered at least three timesdaily for at least seven consecutive days.
 44. The method of claim 39,wherein the composition further comprises a viscosity-increasing agent,surfactant, stabilizing agent/preservative, flavour, fragrance,sweetening agent, bioadhesive agent, or a co-solubilizer.
 45. The methodof claim 44, wherein the composition further comprises a cellulosederivative, acrylic or methacrylic acid polymer or copolymer, ethyleneor propylene glycol, polyethoxylated hydrogenated castor oil, EDTA,sodium benzoate, sodium or potassium sorbate, dextrin, sodium saccharin,or aspartame.
 46. The method of claim 39, wherein the compositionfurther comprises an antibacterial agent, disinfectant agent, antifungalagent, analgesic, anti-inflammatory, emollient, or a local anesthetic.47. A method for treating or preventing inflammation in the oral cavityof a patient comprising: having a patient in need thereof gargle aneffective amount of a composition comprising: (i) from about 0.01 toabout 5 percent by weight of hyaluronic acid, or a pharmaceuticallyacceptable salt thereof, having a molecular weight from about 1.6 toabout 2.2 million daltons; (ii) from about 0.04 to about 15% by weightof a K60 to K100 polyvinylpyrrolidone; and (iii) from about 86 to about98% water, wherein the viscosity of the composition is from about 50 toabout 500 centipoise.
 48. A method for treating or preventinginflammation in the oral cavity of a patient comprising: having apatient in need thereof gargle an effective amount of a compositioncomprising hyaluronic acid or a pharmaceutically acceptable saltthereof; glycyrrhetinic acid or a pharmaceutically acceptable saltthereof; and polyvinylpyrrolidone.
 49. The method of claim 47 or 48,wherein the patient gargles the composition at least twice daily for atleast two consecutive days.
 50. The method of claim 47 or 48, whereinthe patient gargles the composition at least three times daily for atleast four consecutive days.
 51. The method of claim 47 or 48, whereinthe patient gargles the composition at least three times daily for atleast seven consecutive days.
 52. The method of claim 47, wherein thecomposition further comprises glycyrrhetinic acid or a pharmaceuticallyacceptable salt thereof.
 53. The method of claim 47 or 48, wherein thepatient avoids eating or drinking for at least one hour after gargling.54. A method for treating or preventing mucositis in a patientcomprising: administering to a patient in need thereof an effectiveamount of a composition comprising: (i) from about 0.01 to about 5percent by weight of hyaluronic acid, or a pharmaceutically acceptablesalt thereof, having a molecular weight from about 1.6 to about 2.2million daltons; (ii) from about 0.04 to about 15% by weight of a K60 toK100 polyvinylpyrrolidone; and (iii) from about 86 to about 98% water,wherein the viscosity of the composition is from about 50 to about 500centipoise.
 55. A method for treating or preventing mucositis in apatient comprising: administering to a patient in need thereof aneffective amount of a composition comprising hyaluronic acid or apharmaceutically acceptable salt thereof; glycyrrhetinic acid or apharmaceutically acceptable salt thereof; and polyvinylpyrrolidone. 56.The method of claim 54 or 55, wherein the composition is administered atleast twice daily for at least two consecutive days.
 57. The method ofclaim 54 or 55, wherein the composition is administered at least threetimes daily for at least four consecutive days.
 58. The method of claim54 or 55, wherein the composition is administered at least three timesdaily for at least seven consecutive days.
 59. The method of claim 54,wherein the composition further comprises glycyrrhetinic acid or apharmaceutically acceptable salt thereof.
 60. A method for treating painresulting from oral surgery in a patient in need thereof comprising:having a patient in need thereof gargle an effective amount of acomposition comprising: (i) from about 0.01 to about 5 percent by weightof hyaluronic acid, or a pharmaceutically acceptable salt thereof,having a molecular weight from about 1.6 to about 2.2 million daltons;(ii) from about 0.04 to about 15% by weight of a K60 to K100polyvinylpyrrolidone; and (iii) from about 86 to about 98% water,wherein the viscosity of the composition is from about 50 to about 500centipoise.
 61. A method for treating pain resulting from oral surgeryin a patient in need thereof comprising: having a patient in needthereof gargle an effective amount of a composition comprisinghyaluronic acid or a pharmaceutically acceptable salt thereof;glycyrrhetinic acid or a pharmaceutically acceptable salt thereof; andpolyvinylpyrrolidone.
 62. The method of claim 60 or 61, wherein thepatient gargles the composition at least twice daily for at least twoconsecutive days.
 63. The method of claim 60 or 61, wherein the patientgargles the composition at least three times daily for at least fourconsecutive days.
 64. The method of claim 60 or 61, wherein the patientgargles the composition at least three times daily for at least sevenconsecutive days.
 65. The method of claim 60, wherein the compositionfurther comprises glycyrrhetinic acid or a pharmaceutically acceptablesalt thereof.